Radiotherapy augments the immune response to prostate cancer in a time‐dependent manner

Harris, T. J. R.; Hipkiss, Edward L.; Borzillary, Scott; Wada, Satoshi; Grosso, Joseph F.; Yen, Hung-Rong; Getnet, Derese; Bruno, Tullia C.; Goldberg, Monica V.; Pardoll, Drew M.; DeWeese, Theodore L.; Drake, Charles G.

doi:10.1002/pros.20794

Cited by 76 publications

(61 citation statements)

References 33 publications

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“…While the translation of radiation doses and fractionation schemes used in humans to mice is difficult and not very well studied (8,18), prior work has shown that multi-fraction RT is more effective than single-fraction RT when combined with CTLA-4 checkpoint blockade in syngeneic tumor models (19). Additionally, we used a previously described timing approach of the immunomodulatory agent and initiated αPD-1 treatment 6 hours after the second fraction of 8.5 Gy ( Figure 1A) (20). After RT and continuous αPD-1 treatment, we measured the tumor growth kinetics every 2 weeks using noninvasive MRI.…”

Section: Resultsmentioning

confidence: 99%

Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer

et al. 2016

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Section: Resultsmentioning

confidence: 99%

Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer

et al. 2016

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“…31 Indeed, both treatments could induce DNA double-strand breaks that, in turn, produce mutations and neo-antigens generation, promote immunological danger signals 32 and reduce tumor infiltrating immunosuppressive cell populations, such as inhibitory myeloid cells. [23][24][25][33][34][35][36][37][38][39][40] All these events are necessary to trigger antigen-specific CTLs (CD3 C CD8 C ), able to recognize and destroy tumor cells presenting altered and/or overexpressed molecular structures recognized as tumor-associated antigens. 41,42 On these bases, several studies in PC patients have investigated, with contrasting results, the prognostic role of the basal inflammatory status and lymphocytes density in the primary tumor.…”

Section: Discussionmentioning

confidence: 99%

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

Nardone

Botta

Caraglia

et al. 2016

Cancer Biology & Therapy

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Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (C/¡3.93) years, who received salvage radiotherapy with a mean of 69.66 (C/¡ 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (C/¡ 55.82) months, were enrolled in this study. We evaluated, by immunohistochemistry, the intratumoral ( t ) and peripheral stroma ( p ) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3 or PD-1-positive cells on tumor samples taken at the diagnosis ( d ) and relapse times ( R ). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1 C cells. Our analysis revealed that higher CD8 p,RC and lower PD-1 RC TIL scores correlated to a longer bPFS. Higher CD8 p,RC and CCR7 t,RC TIL scores and lower CD45 p,RC and FoxP3 p,RC TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

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“…Nevertheless, they might have utility when used in combination with radiotherapeutic treatments (10,11). Indeed, some of the effects of ionizing radiation are now recognized as contributing to antitumor immunity (12).…”

Section: Introductionmentioning

confidence: 99%

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer

Mondini

Nizard

Tran

et al. 2015

Molecular Cancer Therapeutics

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There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)-based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC-1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8 þ T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8 þ T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by aSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials.

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Radiotherapy augments the immune response to prostate cancer in a time‐dependent manner

Cited by 76 publications

References 33 publications

Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer

Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer

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